High-Relaxivity Molecular MRI Contrast Agent to Target Gb3-Expressing Cancer Cells

Abstract

Targeted contrast agents (CAs) can improve magnetic resonance imaging (MRI) for accurate cancer diagnosis. In this work, we used the Shiga toxin B-subunit (STxB) as a targeting agent, which binds to Gb3, a glycosphingolipid highly overexpressed on the surface of tumor cells. We developed STxB-targeted MRI probes from cyclic peptide scaffolds functionalized with six to nine monoamide DO3A­[Gd­(III)] chelates. The influence of structural constraints on the longitudinal relaxivity (r 1) of the CAs has been studied. The cyclic peptide carrying nine monoamide DO3A­[Gd­(III)] exhibited a r 1 per compound of 32 and 93 mM–1s–1 at 9.4 and 1.5 T, respectively. Its conjugation to the pentameric STxB protein led to a 70 kDa compound with a higher r 1 of 150 and 475 mM–1 s–1 at 9.4 and 1.5 T, respectively. Specific accumulation and cellular distribution of this conjugate in Gb3-expressing cancer cells were demonstrated using immunofluorescence microscopy and quantified by an inductively coupled plasma–mass spectrometry dosage of Gd­(III). Such an agent should enable the in vivo detection by MRI of tumors expressing Gb3 receptors.

AB Toxins as High-Affinity Ligands for Cell Targeting in Cancer Therapy

“…To quantify the amount of conjugate accumulated in cells, they employed an inductively coupled plasma-mass spectrometry dosage of Gd(III). This system may enable the in vivo detection of tumors expressing Gb3 by MRI [ 126 ].…”

Recent Advances in Biomimetic Nanocarrier-Based Photothermal Therapy for Cancer Treatment

“…This bacterial toxin recognizes the globotriaosylceramide (Gb3/CD77) receptor, which is overexpressed on the cell surface in some cancers such as breast, ovarian, colorectal gastric, head and neck cancer, and prostate, among others [119]. The reported overexpression of Gb3 in many cancers opened, a decade ago, the possibility of using the nontoxic subunit B (StxB) of the Shiga toxin coupled to different materials as contrasting agents for cancer imaging and drugs for chemotherapy and more recently for PTT [120][121][122]. Navarro-Palomares and colleagues reported the fabrication of iron oxide nanoparticle cores coated with amorphous silica shells containing rhodamine isothiocyanate (RBITC) dye (Fe 3 O 4 @SiO 2 :RBITC) and functionalized with the StxB to target head and neck cancer (HNC) [123].…”

Nanoscale Contrast Agents for Magnetic Resonance Imaging: A Review

“…These nanoprobes could actively target the tumor-associated membrane markers via an aptamer-mediated recognition, with a specific response to tumor features (acidic pH and H 2 O 2 overformation); precise and enhanced T 1 -weighted MRI signals could be obtained . Additionally, a novel molecular MRI NCA was designed using Gd­(III)-DO3A monoamide chelates, Shiga toxin B-subunit (the targeting agent), and Gb3 (a highly overexpressed glycosphingolipid on the surfaces of the tumor cells) . These probes exhibited high relaxivity with specific accumulation in cancer cells and also had higher cellular distribution in Gb3-expressing cancerous cells, offering suitable alternatives for molecular MRI of tumors ( in vivo ) …”

“…112 Additionally, a novel molecular MRI NCA was designed using Gd(III)-DO3A monoamide chelates, Shiga toxin B-subunit (the targeting agent), and Gb3 (a highly overexpressed glycosphingolipid on the surfaces of the tumor cells). 118 These probes exhibited high relaxivity with specific accumulation in cancer cells and also had higher cellular distribution in Gb3-expressing cancerous cells, offering suitable alternatives for molecular MRI of tumors (in vivo). 118…”

“…118 These probes exhibited high relaxivity with specific accumulation in cancer cells and also had higher cellular distribution in Gb3-expressing cancerous cells, offering suitable alternatives for molecular MRI of tumors (in vivo). 118…”